Several publications and patent documents are cited throughout this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these citations is incorporated by reference herein.
Breast cancer, the malignant disease most frequently diagnosed in postmenopausal Caucasian women living in Northern European countries and in America (Clarke, C. A., et al. (2006) BMC Cancer, 6:170; Botha, J. L. et al. (2003) Europ. J. Cancer, 39:1718-1729), has been recently reported to increase in incidence in women under 40 years of age. Worldwide epidemiological data have reached consensus on the fact that pregnancy before age 20, i.e., early pregnancy, multiple pregnancies, and breastfeeding protect women from developing breast cancer at post menopause (Bouchardy C et al. (2007) British Journal of Cancer, 96: 1743-1746; Brinton L A, et al., (2008) J Natl Cancer Inst 100: 1643-1648). This protective effect has been observed in most ethnic groups and in women carriers of BRCA1 or BRCA2 deleterious mutations (19, 31). However, in women, whose first pregnancy occurred after age 30 or whose breast cancer is diagnosed at or before age 40, protection is not observed. These finding indicate that age at first pregnancy and age at diagnosis are two important criteria for characterizing breast cancer into two succinct risk-categories that respond differently to early life risk factors and differ in their pathogenesis (Jernström H. et al., (1999) Lancet 354(9193):1846-1850). Diagnosis of breast cancer before age 40 is prevalent among Ashkenazi Jewish carriers of BRCA1 or BRCA2 deleterious mutations and in African American women, both groups developing basal-like triple negative tumors of similar pathological and clinical characteristics. The absence of estrogen receptor (ER), progesterone receptor (PR) and Her2 that characterizes these tumors precludes the use of anti-estrogen therapy with selective estrogen receptor modulators (SERMs), such as Tamoxifen, which has been proven to effectively reduce the recurrence of early stage ER-positive breast cancer, or aromatase inhibitors that interfere with estrogen biosynthesis. Current guidelines for risk reduction strategies that are available for unaffected carriers of BRCA1 or BRCA2 deleterious mutations include multi-modality screening and prophylactic mastectomy and oophorectomy (Fatouros, M. et al., (2008) Ann Surg Oncol. 15(1):21-33.). Unfortunately, even if performed at a young age, the specimens obtained from these carriers already exhibit developmental alterations and contain pre-invasive lesions, a clear indication that any preventive measures have to be implemented several years earlier, and before age 20, which represents the optimal period for pregnancy-induced breast cancer prevention. Given the evident limitations of currently existing strategies for breast cancer prevention, it is clear a need exists to more efficiently prevent or inhibit initiation and progression of this devastating disease.